Stable aqueous multivitamin preparations

ABSTRACT

This invention relates to stable aqueous multivitamin preparations in which the vitamin A ingredient is isolated together with the vitamin C and nicotinamide ingredients from other ingredients including the vitamin B1 ingredient.

United States Patent Inventors HideyukiMaekawa Osaka-shi; Shohei Egawa, Amagasaki-shi, both of Japan Appl. No. 731,978 Filed May 24, 1968 Patented Dec. 7, i971 Assignee Shionogi & (30., Ltd.

Osaka, Japan Priority May 25, 1967 Japan 42/33243 STABLE AQUEOUS MULTIVITAMIN PREPARATIONS 2 Claims, 2 Drawing Figs.

US. Cl 424/255, 424/266, 424/280, 424/344 Int. Cl A6lk 15/00 Field of Search 424/280,

[56] References Cited UNITED STATES PATENTS 2,811,483 10/1957 Atero et al 424/280 3,168,440 2/1965 Meyer 424/104 Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin Att0rneyWenderoth, Lind & Ponack ABSTRACT: This invention relates to stable aqueous multivitamin preparations in which the vitamin A ingredient is isolated together with the vitamin C :and nicotinamide ingredients from other ingredients including the vitamin i3 ingredient.

PATENTED DEC 7 l9?! FIG.)

FIGZ

INVENTORS HIDEYUKI MAEKAWA S HOHEI EGAWA BY WM ATTORNEYS 1 2 STABLE AQUEOUS MULTIVITAMIN PREPARATIONS promise. The following table 1 is concerned with an aging test of several aqueous multivitamin preparations adjusted at pH This invention relates to stable aqueous multivitamin 3.0, 4.5 and 6.0. Each sample contains 3 mg. of VA. 7.5 mg. of preparations containing vitamin A, vitamin B,, vitamin C, vitamin D (hereinafter referred to as VD,), 2.5 mg. of V8,, nicotinamide, etc. and, in particular, relates to aqueous mul- 5 3.5 mg. of vitamin B, phosphate (hereinafter referred to as tivitamin preparations containing a stabilized vitamin A in- VB, phosphate), 2.5 mg. of vitamin B lhereinafter referred to gredient. A primary object of the invention is to provide stable as VH 70 mg. of VC and 25 mg. of nicotinamide, respectiveaqueous multivitamin prepara ions C ntaining vitam n A, ly, per 1 ml. of the sample solution. All the samples were vitamin C and nicotinamide as the essential ingredients sealed in glass bottles and stored at 35 C. for 4 weeks. The thereof. A further object of the invention is to provide stable to data prove the unstability of the specific vitamins in admixed aqueous multivitamin preparations containing the above three condition as described supra. ingredients and vitamin B, as the essential ingredients thereof.

Other objects, the gist, the exact nature, the advantages, TABLE and general and specific embodiments of the invention will appear more fully hereinafter by referring to the following a description and the accompanying drawings, in which: Rmmi" s Vitamin FIG. 1 is a vertical sectional view of a container which can VA vc be used for embodying the invention, said container being filled with a multivitamin preparation prepared according to 2; 3;: 2?: :2; the invention: and

FIG. 2 is a vertical sectional view of a further specific conthine!" which can he used embodying the invention, said As seen from the above result, there is no suitable manner to specific container being filled with a multivitamin preparation prevent the decomposition f VA by aging, and Such decom- P p hccol'dihg to the ihvehtlohv position is increased more in plastic containers. For example, It has hitherto been known that Vitamin l C and inthe test with polyethylene-made bottles instead of glass botvitflmiflA (hereinafter fefel'md tOaSVBb VC and VA p ties, the retention of VA was 78.5, 79.4 and 82.3 percent tively) are considerably unstable in aqueous multivitamin respectively (this fact is probably caused oxygen permea. preparations. This phenomenon, as to VB, and VC depends .bili f h l ti t ine on the difference in stable pH region against hydrolysis. On the basis of the above, the inventors investigated the in- Namely, VB, and VC are stable against hydrolysis in different fluence of several vitamins against VA in liquid state (containpH regions thereof, below pH 4.0 for VB, and pH 5.0 to 7.0 ing 2,500 international units/ml. of VA) in glass bottles. The

for VC. Therefore, it is lmposslble to select optimum pH conresults were as in the following table ll.

TABLE II VA retention percentages Composition of samples (mg./m1.

except for VA) C, 4 weeks Room temperature elapsed 1 year elapsed Nicoti- VB VC amide pH 3.0 pH 6.0 pH 3.0 pH 6.0

5 None None 92. 1 00.. 8 90. 5 90. 2

None 70 None 92. 0 93. 8 88. 8 90. 6

5 70 None 90. 5 90. 0 89. 0 87. 5

5 None 25 91. 9 89. 5 89. 5 87. 6

None 70 25 96. 5 97. 0 05. 7 95. 8

None None None 96. 8 97. 2 96. 0 96 2 Control. m. ditions for the two jointly. it is presumed, in the art, that the As seen from the above table II, it is undoubted that the VA gzi ggz gzzfsg 2 1% be accelerated by the decomposl was stabilized by the coexistence of VC and nicotinamide.

Namely, the stability of VA was approximately equal to that of the control, when VC and nicotinamide coexisted, and this inclination reappeared also in a test using polyethylene bottles as in the following table III.

In these circumstances, it is recommended to assure and retain the quality of the aqueous multivitamin preparation in such manner that each vitamin ingredient constituting the preparation is separately paclted so that they are maintained TABLE III VA retention percentages Composition of samples (mg/m l.

except for VA) 35 C, 4 weeks Room temperature elapsed 1 year elapsed Nicoti- VB VC amide pH 3.0 pH 6.0) pH 3.0 pH 6.0

5 None None 86.6 33.3 81. 4 19. 5 None None 86. 2 88. 1 80. 3 82. 8 5 70 N one 84. 0 80. 2 7s. 6 79. o 5 None 25 87.2 82 6 s3 0 82.2 None 70 25 93.2 94 6 91 2 93.2 5 70 25 85.8 83 8 82 2 80. 5 None None None 93.5 94 4 9O 4 92.6

h m apart from euh other and that the Several ingredients are From the above findings, it is clear that the coexistence of VC solved together lh aqueous medlhm Immediately before and nicotinamide is advantageous to the stabilization of VA. use. However, this plan is difficult to realize in actual practice H ltivitamin preparations generally must contain becauseaccording to this P the customers are obhged to VB, as an indispensable ingredient and this vitamin injures VA out multiple compounding procedures Thus, in g 70 coexisting therewith as is clearly seen from tables ll and Ill in the pH of the aqueous multivitamin preparations on the marhi v coexists h VA, vc and nicoiihamid ket is adjusted to stabilize either VB, or VC, or, alternatively cordingly, in aqueous multivitamin preparations, a stable the pH is maintained at 4.0-S.0. These methods are clearly preparation, in particular as to VA, will be obtained by unsatisfactory, because the former sacrifices one or mgre separating the VA ingredient together with VC and nicotinavitamins to a specific vitamin and the latter is only a commide from the VB,. This result was confirmed by the following estimates; Qantas 5fantsaiauaainxraaa'naz are Unit solution Vitamin retention percentages In polyethylene In glass bottles bottles Number pH VA VB, VC VA VB1 VC These results remarkedly show an improvement in the stability of vitamins, particularly of VA, in an aqueous mul-' tivitamin preparation, in comparison with the results of table I. Namely, the retention of VA increased up to 97 percent from 93.6 percent by isolating the VB and by making the VA coexist with the VC and nicotinamide.

The present invention is based on the above findings. The gist of the invention is to divide the aqueous multivitamin preparation into two parts, one (the first liquid) of which contains VA, VC and nicotinamide as the essential ingredients but does not contain VB, and the other (the second liquid) of which contains VB, as the essential ingredient but does not contain VA. The invention is also applicable for VB,-free aqueous multivitamin preparations containing VA as the essential ingredient. In the latter case, the second liquid containing VB, is not necessitated.

The first liquid must contain VA, VC and nicotinamide as its essential ingredients among many vitamins constituting an aqueous multivitamin preparation, but it is optional to add other vitamin(s) except for VB,. On the other hand, the second liquid must contain VB,, but it is optional to add other vitamin(s) except for VA, and VC and nicotinamide can voluntarily be added thereto, if need be. However, since, in general, the optimum ranges of pH condition differ between the first liquid and the second liquid, respectively, the vitamin(s) other than essential and incompatible may be admixed into either of the two liquids in consideration of suitable pH range(s) thereof. Besides, there will be no need to dwell upon other additives such as mineral(s), amino acid(s), pH controlling agent(s), sweetening agent(s), viscosity-increasing agent(s), perfume(s), edible pigment(s) and surfactant(s), because these additives are common auxiliary ingredients in the aqueous multivitamin preparations.

The multivitamin preparations according to the present invention are, in general, divided into two kinds of liquid, and each liquid is packed in a bottle-type container, respectively; and the contents of the respective bottles are admixed together at use by the customer. However, it becomes more convenient, if a duplex container having two independent chambers filled with the unit liquid respectively is used as shown in the following examples.

The invention is further embodied and exemplified by the following examples, but the examples are illustrative only and are not intended to be limitative of the invention.

EXAMPLE I [The first liquid]:

Five hundred mg. (milligrams) of VA palmitate and 1.5 mg. of VD, were dissolved in g. (grams) of polysorbate 80. The solution thus formed was added to 60 ml. (milliliters) of distilled water with stirring to give a homogenous solution. To the solution, there were added g. of VC, 5 g. of nicotinamide and 600 mg. of soluble saccharin to give a homogeneous solution. Then, the solution was adjusted to pH 6.0 with aqueous sodium hydroxide solution, and finally, adjusted to 100 ml. totally by addition of distilled water. The final solution was .10 g. of added and dissolved therein. The solution thus prepared was sealed in 5 3155501, A

[The second liquid]: To 50 ml. of distilled water, there were added 500 mg. of

VB,, 500 mg. of VB, phosphate, 200 mg. of pantothenyl al- .coholand 30 g. of sugar, and the mixture, then, was "homogeneously dissolved. The homogeneous solution thus prepared was adjusted to pH 3.0 with aqueous hydrochloric acid, adjusted to ml. totally with distilled water and sealed in another glass bottle.

The two liquids thus prepared are admixed together immediately before use.-

EXAMPLE 2 [The first liquid]:

Five hundred milligrams of VA palmitate and 1.5 mg. of VD, were dissolved in 10 g. of polysorbate 80. To this solution thus prepared, there was added 60 ml. of distilled water with stirring to fiiye a homogenous solution. To the latter solution, 3 g. of nicotinamide and 20 g. of sugar were then adjusted to pH 6.0 with aqueous sodium hydroxide solution and further adjusted to 100 ml. totally by addition of distilled water.

[The second liquid]:

One hundred milliliters of the second liquid was prepared after the manner of the second liquid in the above example 1 from 500 mg. of VB,, 500 mg. of VB, phosphate, 500 mg. of V8,, 200 mg. of pantothenyl alcohol, 20 g. of L-lysine hydrochloride, 20 g. of sugar, residual amount of distilled water and small amount of aqueous hydrochloric acid for pH regulation.

The two liquids were separately poured into chamber 1 or 2 of the partitioned container 3 and sealed with the screw cap 4 shown in FIG. 1 of the accompanying drawings. The respective contents of the container are admixed together in a suitable dispenser (not shown) before use. The container 3 can be of polyethylene. The contacting surfaces of chambers l and 2 can be essentially integrated by means of a suitable adhesive or the like, if desired.

EXAMPLE 3 The two liquids prepared according to example 1 are filled one by one into one or the other of chambers l I and I2 of the device according to FIG. 2 of the accompanying drawings. In this example, a bottomed inner tube 14 consisting of a suitable plastic material has a horizontal flange portion 15 surrounding the upper open end thereof and hangs on the brim I30 of the main container 13 by the under surface of the said flange. In this way, a space inside the inner tube and another space inside the main container are tightly sealed by the contact between the upper surface of the aforementioned flange I5 and the under surface of a gasket 16 provided at the inside of a cap 17 and by the engagement between the outer wall of the said inner tube 14 and the inner wall of the said main container l3, and by the contact between the under surface of the flange l5 and the brim 13a of the said main container 13, respectively.

At use, the inner tube 14 is pulled out from the main container 13, and the contents in said tube are poured into said main container for mixing. The cap 17 is screwed again on the mouth of the main container to preserve the remaining contents post the use. The inner tube is discarded after the mixing.

Having thus described the invention, what is claimed is:

l. A stable aqueous multivitamin preparation in a unitary package consisting of two kinds of unit liquids, one of which is at about pH 6.0 containing vitamin A, vitamin C and nicotinamide as the essential vitamin ingredients thereof; and the other of which is at about pH 3.0 containing vitamin B1 as the essential vitamin ingredient thereof.

2. A stable aqueous multivitamin preparation which contains vitamin A, vitamin C and nicotinamide as essential vitamin ingredients thereof and is free from vitamin B,, the pH of said preparation being about 6.0.

IOlOl3 0447 

2. A stable aqueous multivitamin preparation which contains vitamin A, vitamin C and nicotinamide as essential vitamin ingredients thereof and is free from vitamin B1, the pH of said preparation being about 6.0. 